Neurobehavioral Family Study of Schizophrenia is a Multiplex Multigenerational Investigation (MGI) of three collaborative RO1s that combine genetic and neurobiologic paradigms to advance the understanding of pathogenesis and detection of genes that modulate susceptibility to schizophrenia (SCZ). Complex genetic mechanisms underlie the susceptibility to SCZ. Paralleling the progress in genetics, neurobiologic studies have identified neural systems that could provide pathophysiologic substrates for focused investigations. We have established a sample of multigenerational multiplex families that were ascertained, phenotypically characterized and genotyped for genome-wide linkage analyses. This sample was examined with a computerized neurocognitive battery that provides complementary quantitative phenotypes to diagnosis. We observed significant heritability for several neurocognitive domains as well as evidence for linkage. Our goal for the renewal application is to capitalize on this unique sample and obtain neuroimaging phenotypes of brain structure and function with Magnetic Resonance Imaging (MRI). We will examine brain structure using volume-based morphometry and connectivity with Diffusion Tensor Imaging (DTI). Functional MRI (fMRI) studies will examine brain circuitry activated in response to neurobehavioral probes. We will follow 300 individuals from the MGI sample for neuroimaging studies. We will also ascertain a new population-based sample of 300 community controls (Specific Aim 1). We will relate the heritability of neuroimaging phenotypes to symptom and neurobehavioral measures and perform multivariate quantitative genetic analyses to identify quantitative phenotypes influenced by the same genes (Specific Aim 2). To establish genetic mechanisms producing the neurobehavioral and neuroimaging phenotypes we will localize new quantitative trait loci through genome-wide association (GWA) analyses and follow-up significant linkage and GWA analysis signals as well as candidate genes identified through ongoing association studies (Specific Aim 3). Specimens will be sent to the NIMH repository for transformation and DNA extraction. Data collection and quality control will be maintained and verified data will be regularly uploaded to the NIMH repository (Specific Aim 4). The MGI augments other samples available with similar measures to confirm and extend present findings. In addition, the phenotypic characterization of participants with neurobehavioral and neuroimaging data will enable evaluation of the relation between genetic influences on neurobiological abnormalities and clinical manifestations. Finding additional potential quantitative markers for genetic vulnerability could improve our understanding of how genes related to brain development and regulation interact with environment in conferring SCZ susceptibility. Such efforts will enhance the integration of neurobiologic and genetic paradigms in human and animal research. In turn, this may pave the way for risk prediction and better treatment. PUBLIC HEALTH RELEVANCE: Schizophrenia is a complex brain disorder that commonly emerges in adolescence and early adulthood and has devastating effects on the individual and family. Understanding the genetic basis of the deficits in brain function is key to early detection and to advance treatments that may improve outcome. The goal of the Multiplex Multigenerational Investigation of the schizophrenia consortium is to integrate neurobehavioral and neuroimaging methods in high-risk families that will yield the data needed for progress in the field.